Involvement of HDAC2-mediated kcnq2/kcnq3 genes transcription repression activated by EREG/EGFR-ERK-Runx1 signaling in bone cancer pain

• Published in: Cell communication and signaling Vol. 22; no. 1; pp. 416 - 31
• Main Authors: Zhang, Zi-Xian, Tian, Yue, Li, Song, Jing, Hong-Bo, Cai, Jie, Li, Min, Xing, Guo-Gang
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27.08.2024; BioMed Central; BMC
• Subjects: Animals; Bone cancer; Bone cancer pain; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Bone Neoplasms - secondary; Cancer pain; Cancer Pain - genetics; Cancer Pain - metabolism; Cancer Pain - pathology; Catheters; Causes of; Complications and side effects; Core Binding Factor Alpha 2 Subunit - genetics; Core Binding Factor Alpha 2 Subunit - metabolism; Development and progression; Dorsal root ganglia; Drug dosages; Epidermal growth factor receptors; Epiregulin; ErbB Receptors - genetics; ErbB Receptors - metabolism; Experiments; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Ganglia, Spinal - metabolism; Ganglia, Spinal - pathology; Gene regulation; Gene silencing; Genes; Genetic aspects; HDAC2 protein; Health aspects; Histone deacetylase; Histone deacetylase 2; Histone Deacetylase 2 - genetics; Histone Deacetylase 2 - metabolism; Humans; Intubation; KCNQ2 Potassium Channel - genetics; KCNQ2 Potassium Channel - metabolism; KCNQ2 protein; KCNQ3 Potassium Channel - genetics; KCNQ3 Potassium Channel - metabolism; KCNQ3 protein; Kv7(KCNQ)/M potassium channels; Laboratory animals; MAP Kinase Signaling System - genetics; MeCP2 protein; Metastases; Methyl CpG binding protein 2; Methyl-CpG binding protein; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Neurons; Pain; Pathogenesis; Potassium; Potassium channels (voltage-gated); Rats; Rats, Sprague-Dawley; Repressor Proteins - genetics; Repressor Proteins - metabolism; Runx1 protein; Signal Transduction - genetics; Sin3 Histone Deacetylase and Corepressor Complex - genetics; Transcription; Transcription activation; Transcription, Genetic; Transcriptional repression; Voltage-gated potassium channels; China; Dorsal root ganglia; Kv7(KCNQ)/M potassium channels; Histone deacetylase 2; Epiregulin; Bone cancer pain; Methyl CpG binding protein 2; Epidermal growth factor receptor; Transcriptional repression
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-024-01797-2

Bone cancer pain (BCP) represents a prevalent symptom among cancer patients with bone metastases, yet its underlying mechanisms remain elusive. This study investigated the transcriptional regulation mechanism of Kv7(KCNQ)/M potassium channels in DRG neurons and its involvement in the development of BCP in rats. We show that HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes, which encode Kv7(KCNQ)/M potassium channels in dorsal root ganglion (DRG), contributes to the sensitization of DRG neurons and the pathogenesis of BCP in rats. Also, HDAC2 requires the formation of a corepressor complex with MeCP2 and Sin3A to execute transcriptional regulation of kcnq2/kcnq3 genes. Moreover, EREG is identified as an upstream signal molecule for HDAC2-mediated kcnq2/kcnq3 genes transcription repression. Activation of EREG/EGFR-ERK-Runx1 signaling, followed by the induction of HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes in DRG neurons, leads to neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats. Consequently, the activation of EREG/EGFR-ERK-Runx1 signaling, along with the subsequent transcriptional repression of kcnq2/kcnq3 genes by HDAC2 in DRG neurons, underlies the sensitization of DRG neurons and the pathogenesis of BCP in rats. These findings uncover a potentially targetable mechanism contributing to bone metastasis-associated pain in cancer patients.